CCT251236 is a cell-based phenotypic high-throughput screening (HTS) chemical probe developed to screen for inhibitors of the HSF1 stress pathway.CCT251236 exhibits antimyeloma activity and inhibits HSF1.

HSP72:19 nM

CCT367766 (0-100 nM; 24 hours) inhibited 17-AAG-induced HSF1-mediated expression of heat shock proteins HSP72 and HSP27 in SK-OV-3 cells in a concentration-dependent manner; CCT367766 also blocked 17-AAG-induced HSPA1A mRNA in a dose-dependent manner; in addition, CCT367766 (0-100 nM; 24 hours) exhibited an ideal balance of in vitro properties while maintaining good cell viability, with pIC50=7.73±0.07 (IC50=19 nM) for inhibiting HSF1-mediated HSP72 induction; in SK-OV-3 cells, the free GI50 was 1.1 nM[1].

CCT367766 (oral; 20 mg/kg; 33 days) showed significant efficacy in mice, with a tumor growth inhibition (%TGI) of 70% based on final tumor volume.After 33 days, there was a 64% reduction in mean tumor weight compared to controls. In addition, the basicity and high volume of distribution of the compound was observed in tumors up to a concentration of 940 nM [1].CCT367766 (oral, 5 or 20 mg/kg) showed free Cav0-24h values of 2.0 nM and 1.2 nM, respectively, in tumor-free immune-competent BALB/c mice [1]; and, in a mouse model of human myeloma xenografts, the CCT251236 (20 mg/kg, po) inhibited the HSF1 pathway and exhibited antimyeloma efficacy in a human myeloma xenograft mouse model [2].